Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, which results directly from the relatively selective loss of nigrostriatal dopaminergic neurons. PD is a heterogeneous disorder of unclear etiology, and although the majority of cases appear sporadic in nature, specific genetic defects have recently been identified in rare familial cases of PD. To date, mutations in three genes are linked to familial PD, alpha-synuclein, parkin, and more recently DJ-1. Mutations in the DJ-1 gene are linked with autosomal recessive early-onset PD in two consanguineous European families. In one affected Dutch family, a 14 kb homozygous genomic deletion within the DJ-1 gene appears to abolish DJ-1 expression. In an Italian family, a homozygous missense mutation, L166P, of the DJ-1 protein is the disease causing entity. This L 166P mutant may result in mislocalization of DJ-1 to mitochondria and may promote loss of protein stability. Disruptions of the DJ-1 gene may result in familial PD, however, the mechanisms by which loss of normal DJ-1 function triggers disease are not known. In fact the normal function of DJ-1 is not yet known. To explore the biologic role of DJ- 1 and understand the actions of the disease causing mutations the following specific aims are proposed: Aim 1: Do DJ- 1 mutants affect the structure and function of DJ- 1? Aim 2: Does DJ-1 bind or interact with other proteins implicated in the pathogenesis of PD? Aim 3: What is the effect of loss of function or overexpression of DJ- 1 on cell viability? Aim 4: What is the expression pattern of DJ-1 in normal and Parkinson's disease tissue? Aim 5: Identification of proteins that interact with DJ-1. On conclusion of this project we hope to better understand the biologic role of DJ-1, the consequences of loss of DJ-1 activity and an understanding of how or if DJ- 1 interact with other signaling pathways already associated with PD.